A facile synthesis of lentiginosine analogues based on a highly regio- and diastereoselective allylic amination using chlorosulfonyl isocyanate

Article abstract of DOI:10.1002/ejoc.200901443

The concise synthesis of the lentiginosine analogues pyrrolidine alkaloid 2 and pyrroloazepine alkaloid 3 has been achieved from, inexpensive and. readily available D-lyxose. The key steps in the synthesis included, regio- and diastereoselective amination

Full text of DOI:10.1002/ejoc.200901443

FULL PAPER
DOI: 10.1002/ejoc.200901443
A Facile Synthesis of Lentiginosine Analogues Based on a Highly Regio- and
Diastereoselective Allylic Amination Using Chlorosulfonyl Isocyanate
In Su Kim,[a] Qing Ri Li,[b] Guang Ri Dong,[b] Yoo Chang Kim,[b] Yeon Ju Hong,[b]
Momi Lee,[b] Ki-Whan Chi,[a] Joa Sub Oh,[b] and Young Hoon Jung*[b]
Keywords: Azasugars / Synthetic methods / Inhibitors / Amination / Alkaloids
The concise synthesis of the lentiginosine analogues pyrroliz-
idine alkaloid 2 and pyrroloazepine alkaloid 3 has been
was synthesized by the regio- and diastereoselective amin-
ation of anti-3,4-tribenzyl ether 7 using chlorosulfonyl isocy-
anate. The reaction of 7 with chlorosulfonyl isocyanate in tol-
uene at 0 °C afforded 6 exclusively with a diastereoselectivity
of 26:1 in 84% yield. These results can be explained by the
neighboring-group effect, which leads to retention of the
stereochemistry.
achieved from inexpensive and readily available
D-lyxose.
The key steps in the synthesis included regio- and diastereo-
selective amination, inter- or intramolecular olefin metathe-
sis, and Appel cyclization. The anti-3,4-amino alcohol 6, es-
sential for the preparation of the title compounds 2 and 3,
Although there has been considerable research in the
area of natural alkaloids such as lentiginosine (5,6-ring sys-
tem), unnatural analogues of lentiginosine, that is, pyrroliz-
idines (5,5-ring system) and pyrroloazepines (5,7-ring sys-
tem), remain relatively unexplored. Consequently, the syn-
thesis of polyhydroxylated pyrrolizidine and pyrroloazepine
has attracted considerable attention. This study focused on
the synthesis of pyrrolizidine alkaloid 2 and pyrroloazepine
alkaloid 3 as new glycosidase inhibitors (Figure 1).
Introduction
Polyhydroxylated alkaloids (azasugars or iminosugars)
are among the most interesting recent discoveries in the
field of natural products. They are distributed widely in
many plants and microorganisms[1] and have been reported
to inhibit a range of glycosidases in a reversible or competi-
tive manner due to their structural resemblance to the sugar
moiety of natural substrates.[2] Most of these glycosidase
inhibitors have attracted considerable interest and demand
on account of their remarkable therapeutic potential in
many diseases, such as viral or bacterial infections, diabetes,
obesity, and cancer.[3] As a consequence, a variety of natural
or non-natural analogues of polyhydroxylated alkaloids
have been prepared and evaluated for clinical applications.[4]
For example, two N-alkylated derivatives of deoxynojirimy-
Figure 1. Structures of lentiginosine and its analogues.
cin, miglitol (GlysetTM
) and N-butyldeoxynojirimycin
(ZavescaTM), are currently used as drugs for the treatment
of type II diabetes and Gaucher’s disease, respectively.[5]
As part of an ongoing research program aimed at the
development of an amination methodology using chlorosul-
fonyl isocyanate (CSI)[6] and its application to the total syn-
thesis of polyhydroxylated alkaloids,[7] we recently reported
a facile approach to the construction of indolizidine alk-
aloid (–)-lentiginosine (1) based on the regio- and diastereo-
selective allylic amination of polybenzyl ethers using chlo-
rosulfonyl isocyanate.[8]
Results and Discussion
The retrosynthetic analysis of 2 and 3 is outlined in
Scheme 1. The five-membered ring of the pyrrolizidine core
would be constructed from pyrrolidine 4 by intramolecular
ring-closing metathesis after chemoselective Pd-catalyzed
deprotection of the N-Cbz moiety in 5 and N-alkylation
with allyl bromide. However, the ring-closing metathesis
protocol was far less effective in the synthesis of the pyr-
roloazepine core. Therefore, it was envisaged that the seven-
membered ring of the pyrroloazepine core could be pre-
pared by Appel cyclization after intermolecular olefin me-
tathesis between compound 5 and its alkene partner. The
common intermediate 5 could be prepared by the intramo-
lecular cyclization of compound 6, which, in turn, would
come from the regio- and diastereoselective introduction of
[a] Department of Chemistry, University of Ulsan,
Ulsan 680-749, Korea
[b] College of Pharmacy, Sungkyunkwan University,
Suwon 440-746, South Korea
Fax: +82-31-290-7773
E-mail: yhjung@skku.ac.kr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901443.
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Y. H. Jung et al.
FULL PAPER
NHCbz into cinnamyl polybenzyl ether 7 using chlorosulfo-
nyl isocyanate. This approach would allow the two dihy-
droxylated alkaloids to be generated from the same inter-
mediate 5 in relatively few synthetic steps.
The total synthesis of pyrrolizidine alkaloid 2 was
achieved by starting from the benzylated pyranose 8 pre-
pared from commercially available -lyxose according to a
methodology reported in the literature.[9] Wittig reaction of
compound 8 with the DMSO anion in THF at 45 °C af-
forded the olefin 9 as a 3.1:1 mixture of (Z)/(E) isomers in
94% yield (Scheme 2). The hydroxy moiety of compound 9
was then converted into the bromide 7 with carbon tetra-
bromide, triphenylphosphane, and triethylamine in 89%
yield. Treatment of the anti-3,4-tribenzyl ether 7 with chlo-
rosulfonyl isocyanate in toluene at 0 °C for 24 h followed by
desulfonylation using an aqueous solution of 25% sodium
sulfite afforded the anti-3,4-amino alcohol 6 with an excel-
lent diastereoselectivity of 26:1 in 84% yield.
The intramolecular cyclization of compound 6 with po-
tassium tert-butoxide provided the corresponding pyrrol-
idine 5 in 95% yield. Various deprotection conditions, such
as BBr3,[10] hydrogenation, and KOH[11] were attempted for
the chemoselective removal of the Cbz moiety on the pyr-
rolidine ring in 5, but with limited/no success. Pd-catalyzed
Scheme 1. Retrosynthetic analysis of 2 and 3.
Scheme 2. Total synthesis of (1R,2R,7aR)-1,2-dihydroxypyrrolizidine (2).
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Synthesis of Lentiginosine Analogues
N-Cbz deprotection with triethylsilane gave the desired Table 1. Intermolecular olefin metathesis of the disubstituted alk-
ene 5 and terminal olefins 14 and 15.[a]
product 10, concomitant with the isomerization of the (Z)/
(E) olefin mixtures 5 to produce the (Z) olefin exclu-
sively.[12,13] Allylation of the pyrrolidine 10 under standard
conditions (allyl bromide, K2CO3, and THF) proceeded
cleanly to afford in 82% yield the diene compound 4 re-
quired for ring-closing metathesis. Treatment of compound
4 with Grubbs II catalyst in toluene at reflux afforded the
pyrrolizidine core 11 in 57% yield. Finally, catalytic hydro-
genation provided the pyrrolizidine alkaloid (1R,2R,7aR)-
1,2-dihydroxypyrrolizidine (2) in quantitative yield. The
spectroscopic data (1H and 13C NMR) and specific rotation
of the synthetic sample are identical to those reported in
the literature.[14]
Entry Catalyst[b] Mol-% Olefin (equiv.) T [°C] Yield[c] [%]
1
2
3
4
5
6
A
B
C
B
B
B
20
20
20
20
20
30
14 (5)
14 (5)
14 (5)
15 (5)
15 (10)
15 (10)
80
80
80
100
100
100
5
12
trace
44
56
63
According to previous work, Grubbs II catalyst was first
used with compound 12 under a range of reaction condi-
tions to give the pyrroloazepine core 13. However, these
attempts were unsuccessful and led to the recovery of the
starting material and a small amount of intermolecular ole-
fination byproducts. Extended reaction times resulted in de-
composition of the starting material. Similar results were
obtained when the reaction was carried out with Grubbs I
and Hoveyda–Grubbs catalysts (Scheme 3, Figure 2).[15] In
view of these unsuccessful results, we turned our attention
to the intermolecular metathesis reaction between the com-
mon intermediate 5 and alkene partners 14 and 15. The
reaction conditions for the intermolecular olefination reac-
tion were then optimized, and the results are summarized
in Table 1.
[a] All reactions were carried out in toluene for 48 h. [b] See Fig-
ure 2 for the structures of the catalysts. [c] Isolated yield of the pure
materials.
converted into the corresponding alkene 17 as a 3:1 mixture
of (E)/(Z) isomers in 63% yield (Entry 6).
To complete the synthesis of pyrroloazepine 3, the olefin
17 was treated with tetrabutylammonium fluoride (TBAF)
to give the primary alcohol 16 (Scheme 4). One-pot deben-
zylation and reduction of the olefin 16 by hydrogenation
provided trihydroxylated pyrrolidine alkaloid 18 in 72%
yield. Finally, Appel cyclization[16] of compound 18 and
subsequent resin purification provided the 5,7-bicyclic dihy-
droxylated alkaloid 3. To the best of our knowledge this is
the first report of the total synthesis of compound 3.
Scheme 3. Ring-closing metathesis approach for the synthesis of
13.
Scheme 4. Total synthesis of (1R,2R,9aR)-octahydro-1H-pyr-
rolo[1,2-a]azepine-1,2-diol (3).
Figure 2. Grubbs I and II catalysts and Hoveyda–Grubbs catalyst
for intermolecular olefin metathesis.
The reaction of compound 5 and 4-penten-1-ol (14) un-
der Grubbs I, II or Hoveyda–Grubbs catalysis gave the cor-
responding product 16 in low yield (Entries 1–3). However,
the desired product 17 was obtained in 44% yield when the
Conclusions
We have demonstrated the total synthesis of the lentigin-
terminal olefin 15 was used with 20 mol-% of Grubbs II osine analogues pyrrolizidine alkaloid 2 and pyrroloazepine
catalyst (Entry 4). An increased loading of compound 15 alkaloid 3 starting from readily available -lyxose by the
was more effective under otherwise identical conditions regio- and diastereoselective allylic amination of anti-3,4-
(Entry 5). Finally, when 30 mol-% of Grubbs II catalyst was tribenzyl ether 7 using chlorosulfonyl isocyanate, intra- or
used in toluene at 100 °C, the disubstituted alkene 5 was intermolecular olefin metathesis, and Appel cyclization. It
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NMR (125 MHz, CDCl3): δ = 58.42, 62.90, 72.21, 72.26, 76.47,
83.66, 86.27, 127.79, 127.82, 127.88, 127.94, 127.96, 128.62, 128.67,
is believed that this synthetic strategy can be applied to the
preparation of a range of polyhydroxylated alkaloids or
other natural products containing a ring nitrogen atom.
129.09, 138.44, 138.51 ppm. IR (neat): ν = 3344, 1592, 1418, 1121,
˜
1041 cm–1. HRMS (FAB): calcd. for C21H24NO2 [M + H]+
322.1807; found 322.1812.
Experimental Section
(1R,2R,7aR)-1,2-Dihydroxypyrrolizidine (2): A 6  solution of
aqueous HCl (1.5 mL) and 10% Pd/C (20 mg, 0.02 mmol) was
added to a solution of 11 (45 mg, 0.14 mmol) in EtOH (7 mL). The
reaction mixture was shaken in a Parr apparatus under hydrogen
(60 psi) for 24 h. The resulting mixture was filtered through a Celite
pad and concentrated in vacuo. The residue was purified by elution
through a DOWEX-50Wx8 (H+ form) ion-exchange resin by using
0.5  aqueous NH4OH as eluent to afford 20 mg (100%) of 2 as a
white solid. Rf = 0.30 (CH2Cl2/MeOH/30%NH4OH, 5:5:2). M.p.
166–167 °C. [α]2D5 = +10.1 (c = 1, MeOH). 1H NMR (300 MHz,
D2O): δ = 1.75–1.80 (m, 1 H), 1.84–1.89 (m, 1 H), 1.91–1.99 (m, 1
H), 2.00–2.15 (m, 1 H), 2.89 (dd, J = 12.0, 5.7 Hz, 1 H), 2.96 (dd,
J = 12.0, 5.1 Hz, 1 H), 3.28 (dt, J = 11.4, 5.7 Hz, 1 H), 3.51 (dd, J
= 12.0, 5.7 Hz, 1 H), 3.59 (dd, J = 12.0, 7.2 Hz, 1 H), 3.94 (t, J =
4.8 Hz, 1 H), 4.20 (dd, J = 5.1, 4.8 Hz, 1 H) ppm. 13C NMR
(125 MHz, D2O): δ = 25.14, 29.18, 56.50, 57.49, 71.93, 76.34,
79.20 ppm. HRMS (CI): calcd. for C7H14NO2 [M + H]+ 144.1024;
found 144.1024.
General Procedures: Commercially available reagents were used
without additional purification unless otherwise stated. All an-
hydrous solvents were distilled from CaH2, P2O5, or Na/benzo-
phenone prior to reaction. All reactions were performed under ni-
trogen or argon. Melting points were measured with a Gallenkamp
or Electrothermal IA9300 melting-point apparatus. NMR spectra
(1H and 13C NMR) were recorded with a Varian Unity Inova
500 MHz spectrometer in CDCl3 solutions, and chemical shifts are
reported as parts per million (ppm) relative to residual CHCl3 (δH
= 7.26 ppm) and CDCl3 (δC = 77.0 ppm) as internal standards.
Resonance patterns are reported with the following notations: s
(singlet), d (doublet), t (triplet), q (quartet), and m (multiplet). In
addition, the notation br. is used to indicate a broad signal. Cou-
pling constants (J) are reported in Hertz (Hz). IR spectra were
recorded with a Nicolet 205 or Bruker Vector 22 infrared spectro-
photometer and are reported in cm–1. Optical rotations were
measured with a Jasco P1020 polarimeter. Thin-layer chromatog-
raphy was carried out on plates coated with Kieselgel 60F254
(Merck). For flash column chromatography, E. Merck Kieselgel 60
(230–400 mesh) was used. High-resolusion mass spectra (HRMS)
were recorded with a JEOL, JMS-505 or JMS-600 spectrometer.
Benzyl (2R,3R,4R)-3,4-Bis(benzyloxy)-2-[5-(tert-butyldimethylsilyl-
oxy)pent-1-enyl]pyrrolidine-1-carboxylate (17): tert-Butyldimethyl-
(pent-4-enyloxy)silane (15; 1.12 g, 5.58 mmol) and second-genera-
tion Grubbs catalyst (0.141 g, 0.167 mmol) were added to a stirred
solution of 5 (0.29 g, 0.558 mmol) in anhydrous toluene (5.6 mL)
under N2. The reaction mixture was stirred at 100 °C for 48 h. The
resulting mixture was filtered through a Celite pad and concen-
trated in vacuo. The residue was purified by flash column
chromatography (hexanes/EtOAc, 8:1) to afford 0.217 g (63%) of
17 as a pale-yellow oil. Rf = 0.30 (hexanes/EtOAc, 6:1). [α]2D5 = +1.2
(c = 0.14, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 0.06 (s, 6 H),
0.88 (s, 9 H), 1.42–1.64 (m, 2 H), 2.00–2.16 (m, 2 H), 3.50–3.68 (m,
3 H), 3.75–3.80 (m, 2 H), 4.04 (t, J = 2.5 Hz, 1 H), 4.40–4.65 (m,
4 H), 5.09 (br. m, 1 H), 5.15 (d, J = 12.5 Hz, 1 H), 5.17 (d, J =
12.5 Hz, 1 H), 5.47–5.61 (m, 2 H), 7.26–7.37 (m, 15 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = –5.04, –4.99, 18.56, 26.19, 26.20,
28.66, 29.93, 32.38, 36.14, 50.86, 62.73, 62.98, 64.88, 67.00, 71.62,
71.84, 76.67, 80.36, 81.41, 85.69, 86.87, 127.83, 127.89, 128.04,
128.05, 128.10, 128.59, 128.69, 128.71, 129.36, 132.81, 137.09,
137.88, 137.89, 155.44 ppm. HRMS (FAB): calcd. for
C37H50NO5Si [M + H]+ 616.3458; found 616.3456.
(Z)-(2R,3R,4R)-3,4-Bis(benzyloxy)-1-(prop-2-enyl)-2-styrylpyrrol-
idine (4): Potassium carbonate (0.29 g, 2.08 mmol) and allyl bro-
mide (0.18 mL, 2.08 mmol) were added to a stirred solution of 10
(0.20 g, 0.52 mmol) in anhydrous THF (1.7 mL) at room tempera-
ture under N2. The reaction mixture was stirred at 45 °C for 4 h
and quenched with H2O (1 mL). The aqueous layer was extracted
with EtOAc (5 mL). The organic layer was washed with H2O and
brine, dried with MgSO4, and concentrated in vacuo. The residue
was purified by flash column chromatography (hexanes/EtOAc,
6:1) to afford 0.18 g (82%) of 4 as a colorless syrup. Rf = 0.30
(hexanes/EtOAc, 5:1). [α]2D5 = –249.1 (c = 0.2, CHCl3). 1H NMR
(500 MHz, CDCl3): δ = 2.44–2.47 (br., 1 H), 2.55–2.58 (br., 1 H),
3.17–3.20 (br., 1 H), 3.39 (br. d, J = 10.0 Hz, 1 H), 3.49–3.53 (br.,
1 H), 3.97–4.02 (br., 2 H), 4.49 (d, J = 12.0 Hz, 1 H), 4.56 (d, J =
11.5 Hz, 1 H), 4.59 (d, J = 11.5 Hz, 1 H), 4.62 (br. s, 1 H), 5.02
(br., 1 H), 5.08 (dd, J = 17.0, 1.0 Hz, 1 H), 5.72–5.81 (m, 2 H),
6.78 (d, J = 11.5 Hz, 1 H), 7.23–7.44 (m, 15 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 56.58, 57.00, 71.48, 72.59, 82.10, 90.09,
117.57, 127.29, 127.91, 128.01, 128.16, 128.35, 128.55, 128.60,
Benzyl (2R,3R,4R)-3,4-Bis(benzyloxy)-2-(5-hydroxypent-1-enyl)pyr-
rolidine-1-carboxylate
(16):
Tetrabutylammonium
fluoride
129.16, 132.74, 133.98, 135.39, 138.26 ppm. IR (neat): ν = 3342,
˜
(0.71 mL, 0.714 mmol, 1.0  in THF) was added to a stirred solu-
tion of 17 (0.22 g, 0.357 mmol) in anhydrous THF (1.8 mL) under
N2. The reaction mixture was stirred at room temperature for 8 h
and quenched with a solution of aqueous saturated NaHCO3
(1 mL). The aqueous layer was extracted with EtOAc (5 mLϫ2).
The organic layer was washed with H2O and brine, dried with
MgSO4, and concentrated in vacuo. The residue was purified by
flash column chromatography (hexanes/EtOAc, 2:1) to afford
0.136 g (76%) of 16 as a colorless syrup. Rf = 0.25 (hexanes/EtOAc,
2:1). [α]2D5 = +7.0 (c = 0.26, CHCl3). 1H NMR (500 MHz, CDCl3):
δ = 1.50–1.69 (m, 2 H), 2.00–2.20 (m, 3 H), 3.50–3.64 (m, 3 H),
3.71–3.91 (m, 2 H), 4.04 (d, J = 2.5 Hz, 1 H), 4.35–4.64 (m, 4 H),
5.01–5.22 (m, 3 H), 5.50–5.61 (m, 2 H), 7.20–7.39 (m, 15 H) ppm.
2362, 1593, 1420, 1121, 1041 cm–1. HRMS (FAB): calcd. for
C29H32NO2 [M + H]+ 426.2433; found 426.2438.
(1R,2R,7aR)-1,2-Bis(benzyloxy)-2,3,5,7a-tetrahydro-1H-pyrrolizine
(11):[17] Second-generation Grubbs catalyst (24 mg, 0.028 mmol)
was added to a stirred solution of 4 (0.12 g, 0.28 mmol) in anhy-
drous toluene (2.8 mL) under N2. The reaction mixture was heated
at reflux for 24 h. The resulting mixture was filtered through a Ce-
lite pad and concentrated in vacuo. The residue was purified by
flash column chromatography (CHCl3/MeOH, 15:1) to afford
52 mg (57%) of 11 as a pale-yellow oil. Rf = 0.28 (CHCl3/MeOH,
15:1). [α]2D5 = +20.6 (c = 0.1, CHCl3). 1H NMR (500 MHz, CDCl3):
δ = 2.74 (dd, J = 10.0, 7.0 Hz, 1 H), 3.41 (dd, J = 10.0, 5.0 Hz, 1
H), 3.48–3.53 (m, 1 H), 3.83–3.89 (m, 2 H), 4.17–4.21 (m, 2 H), 13C NMR (125 MHz, CDCl3): δ = 28.67, 32.06, 50.92, 62.55, 64.90,
4.17–4.21 (m, 2 H), 4.56 (d, J = 12.0 Hz, 1 H), 4.62 (d, J = 12.0 Hz, 67.05, 71.65, 80.34, 81.29, 85.54, 86.81, 127.89, 128.09, 128.13,
1 H), 4.65 (s, 2 H), 5.75 (s, 2 H), 7.27–7.39 (m, 10 H) ppm. 13C 128.62, 128.71, 128.73, 128.99, 131.51, 132.24, 132.95, 137.09,
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Synthesis of Lentiginosine Analogues
575–591; d) P. S. Johnson, H. E. Lebovitz, R. F. Coniff, D. C.
Simonson, P. Raskin, C. L. Munera, J. Clin. Endocrinol. Metab.
1998, 83, 1515–1522; e) T. Tsuruoka, H. Fukuyasu, M. Ishii,
T. Usui, S. Shibahara, S. Inouye, J. Antibiot. 1996, 49, 155–
161; f) G. K. Ostrander, N. K. Scribner, L. R. Rohrschneider,
Cancer Res. 1988, 48, 1091–1094; g) R. A. Gruters, J. J. Neefjes,
M. Tersmette, R. E. Y. de Goede, A. Tulp, H. G. Huisman, F.
Miedema, H. L. Ploegh, Nature 1987, 330, 74–77.
137.85, 155.12 ppm. HRMS (FAB): calcd. for C31H36NO5 [M +
H]+ 502.2593; found 502.2599.
(2R,3R,4R)-2-(5-Hydroxypentyl)pyrrolidine-3,4-diol (18):
A 6 
solution of aqueous HCl (1.2 mL) and 10% Pd/C (20 mg,
0.02 mmol) were added to a solution of 16 (0.12 g, 0.239 mmol) in
MeOH (2.4 mL). The reaction mixture was shaken in a Parr appa-
ratus under hydrogen (60 psi) for 24 h. The resulting mixture was
filtered through a Celite pad and concentrated in vacuo. The resi-
due was purified by elution through a DOWEX-50Wx8 (H+ form)
ion-exchange resin by using 0.5  aqueous NH4OH as eluent to
afford 32.5 mg (72%) of 18 as a white solid. Rf = 0.26 (CH2Cl2/
[4] V. H. Lillelund, H. H. Jensen, X. Liang, M. Bols, Chem. Rev.
2002, 102, 515–553, and references therein.
[5] a) B. Junge, M. Matzke, J. Stoltefuss in Handbook of Experi-
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L. J. Scott, C. M. Spencer, Drugs 2000, 59, 521–549.
1
MeOH/30%NH4OH, 5:5:0.8). [α]2D5 = –8.6 (c = 0.08, MeOH). H
NMR (500 MHz, D2O): δ = 1.27–1.52 (m, 7 H), 1.61–1.67 (m, 1
H), 2.79–2.85 (m, 2 H), 3.05 (dd, J = 12.0, 6.0 Hz, 1 H), 3.53 (t, J
= 6.5 Hz, 2 H), 3.67 (dd, J = 5.5, 3.5 Hz, 1 H), 4.07 (dt, J = 6.0,
2.5 Hz, 1 H) ppm. 13C NMR (125 MHz, D2O): δ = 25.11, 26.00,
31.29, 32.63, 50.61, 61.93, 64.48, 77.46, 82.30 ppm. HRMS (FAB):
calcd. for C9H20NO3 [M + H]+ 190.1443; found 190.1448.
[6] a) G. R. Dong, Q. R. Li, S. H. Woo, I. S. Kim, Y. H. Jung,
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Tetrahedron 2002, 58, 4395–4402; h) J. D. Kim, M. H. Lee, G.
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(1R,2R,9aR)-Octahydro-1H-pyrrolo[1,2-a]azepine-1,2-diol (3): CCl4
(15 µL, 0.159 mmol), PPh3 (42 mg, 0.159 mmol), and Et3N (22 µL,
0.159 mmol) were added to a stirred solution of 18 (15 mg,
0.079 mmol) in anhydrous DMF (0.6 mL) under N2. The reaction
mixture was stirred at room temperature for 36 h and quenched
with MeOH (1 mL). The resulting mixture was concentrated in
vacuo. The residue was purified by elution through a DOWEX-
50Wx8 (H+ form) ion-exchange resin by using 0.5  aqueous
NH4OH as eluent and flash column chromatography (CH2Cl2/
MeOH/30%NH4OH, 60:9:1) to afford 6.9 mg (51%) of 3 as a white
solid. Rf = 0.23 (CH2Cl2/MeOH/30%NH4OH, 60:9:1). [α]2D5
=
1
+27.7 (c = 0.2, MeOH). H NMR (500 MHz, CD3OD): δ = 1.60–
1.93 (m, 7 H), 2.10–2.18 (m, 1 H), 2.85–2.92 (m, 1 H), 3.00–3.07
(m, 1 H), 3.20–3.33 (m, 3 H), 3.78 (dd, J = 4.5, 3.0 Hz, 1 H), 4.07
(dt, J = 4.5, 3.0 Hz, 1 H) ppm. 13C NMR (125 MHz, CD3OD): δ
= 25.37, 26.12, 26.67, 30.11, 55.35, 61.48, 73.08, 74.99, 82.83 ppm.
HRMS (FAB): calcd. for C9H18NO2 [M + H]+ 172.1338; found
172.1337.
Supporting Information (see also the footnote on the first page of
this article): 1H and 13C NMR spectra for compounds 2–4, 11, and
16–18.
Acknowledgments
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This research was supported by a Korean Research Foundation
Grant funded by the Korean Government (MOEHRD) (KRF-
2006-311-E00613) and the Seoul Research and Business Develop-
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Received: December 11, 2009
Published Online: January 27, 2010
Eur. J. Org. Chem. 2010, 1569–1573
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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